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C I R C A D I A N R H Y T H M S I N E N D O C R I N O L O G Y A N D M E TA B O L I S M

The human stress response

Georgina Russell* and Stafford Lightman   *
Abstract | The human stress response has evolved to maintain homeostasis under conditions of
real or perceived stress. This objective is achieved through autoregulatory neural and hormonal
systems in close association with central and peripheral clocks. The hypothalamic–pituitary–
adrenal axis is a key regulatory pathway in the maintenance of these homeostatic processes.
The end product of this pathway — cortisol — is secreted in a pulsatile pattern, with changes
in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and
pulsatility is maintained. Although the initial rise in cortisol follows a large surge in adrenocortico­
tropic hormone levels, if long-​term inflammatory stress occurs, adrenocorticotropic hormone
levels return to near basal levels while cortisol levels remain raised as a result of increased adrenal
sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-​
releasing hormone-​dominant to arginine vasopressin-​dominant, and cortisol levels remain raised
due at least in part to decreased cortisol metabolism. Acute elevations in cortisol levels are
beneficial to promoting survival of the fittest as part of the fight-​or-flight response. However,
chronic exposure to stress results in reversal of the beneficial effects, with long-​term cortisol
exposure becoming maladaptive, which can lead to a broad range of problems including the
metabolic syndrome, obesity , cancer, mental health disorders, cardiovascular disease and
increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states
and glucocorticoid-​based therapeutics are also discussed.

Zeitgebers
Cues that entrain or
synchronize the body’s
24-h cycle
Ultradian rhythms
Biological rhythms that occur
with a frequency of <24 h.
Circadian clock
A biochemical oscillator
with phases synchronized with
solar time.
Translational Health Sciences,
Dorothy Hodgkin Building,
Bristol Medical School,
University of Bristol,
Bristol, UK.
*e-​mail: Georgina.russell@
bristol.ac.uk; Stafford.
Lightman@bristol.ac.uk
https://doi.org/10.1038/
s41574-019-0228-0
In response to a stressor, the body activates multiple coor­
dinated and dynamic processes to restore homeo­stasis,
preserve life and ultimately achieve evolutionary success
for the species. The importance of endocrine systems
in this homeostatic regulation has been known since
the early studies of Hans Selye1 in the 1930s, when acti­
vation of the sympatho–adrenomedullary (SAM) and
hypothalamic–pituitary–adrenal (HPA) axes was des­
cribed in response to physical injury and exertion as well
as perceived psychological threats. Interestingly, antici­
pation of these threats is itself a very potent activator of
these systems2. Homeostatic processes also interact with
internal and external Zeitgebers such as the light–dark
cycle and internal body clocks3,4. These internal clocks
enable the body to anticipate regular changes in the
environment to ensure optimal fitness across the 24 h
and thus the best chance for survival5. The human stress
response is an additional homeostatic mechanism that
provides a better chance of survival when the body is
under threat and mobilizes neural and hormonal net­
works to optimize cognitive, cardiovascular, immuno­
logical and metabolic function (Fig. 1). In this Review we
discuss how the HPA axis helps achieve and maintain
homeostasis. We will show how it utilizes rhythmic 24-h
patterns of secretion to achieve appropriate tissue activity
at different times of the day, and faster ultradian rhythms
to optimize tissue-​specific glucocorticoid signalling
and maintain the rapid reactivity necessary for a stress
response system.
Circadian clocks
In the absence of internal or external stressors, the
integrity of physiological systems is maintained in a
dynamic fashion over 24 h by an internal circadian clock
that antici­pates the changes occurring over the 24-h day.
In the past, the neurocentric hierarchical view was that
body rhythms were controlled from a master clock in the
hypothalamic suprachiasmatic nucleus (SCN)6. Now, it
is very clear that peripheral clocks also exist in most, if
not all, tissues of the body, which have their own auton­
omous transcriptional autoregulatory feedback loops7.
The core clock genes, both in the SCN and peripheral
clocks, are CLOCK and BMAL1. Activation of these
genes generates a heterodimer of BMAL1 with either
CLOCK or NPAS2, which bind at promoter elements
called E-​boxes to drive genes encoding period 1–3, crypto­
chrome 1–2 and nuclear receptor subfamily 1–2. The
resultant proteins then feedback to repress BMAL1 by a
series of feedback loops, generating a 24-h rhythm8,9 that
allows time-​of-day-​dependent regulation of downstream
genomic pathways. This rhythmicity is crucial for homeo­
stasis. The body can only behave optimally when all

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Key points
• The hypothalamic–pituitary–adrenal (HPA) axis is a key system that synchronizes the
stress response with circadian regulatory processes.
• Regulation of the HPA axis is very dynamic with both ultradian and circadian
oscillations.
• Short-​term and longer-​term stress result in different regulatory mechanisms involving
hypothalamic, pituitary and adrenal activity, as well as cortisol metabolism.
• Chronic elevation and nonphysiological patterns of cortisol result in poor cognitive,
metabolic and immune function.
biological rhythms are in synchrony. However, with our
increasingly chaotic lifestyles this orderly physiological
regulation is steadily being disrupted, which can result
in chronodisruption4,10. This desynchronization between
cellular oscillators in the SCN and peripheral tissues
can manifest as negative health outcomes in the form
of cardiovascular, metabolic, cognitive and immune
dysfunction4,10–14.
HPA axis and circadian rhythmicity
The HPA axis is critical for life and is a major part of
our homeostatic regulatory system15. The output of this
system is the endogenous glucocorticoid corticosterone
(in rodents) or cortisol (in humans), which are collec­
tively referred to as CORT. Glucocorticoids have diverse
and far reaching effects, which is why they are such suc­
cessful therapeutic agents; however, this diversity is a
double-​edged sword and excess levels of glucocorticoids
result in a myriad of unwanted adverse effects, including
diabetes mellitus, hypertension, immune dysregulation
and osteoporosis16. Glucocorticoids exhibit powerful
anti-​inflammatory functions both at a whole-​cell and
at a transcriptional level. They can induce apoptosis of
T lymphocytes, neutrophils, basophils and eosinophils17.
They also regulate multiple proinflammatory genes
encoding cytokines, chemokines and inflammatory
enzymes associated with repression of AP1 and nuclear
factor-​κB (NF-​κB) transcription18. Glucocorticoids also
inhibit antigen presentation19,20, major histocompatibil­
ity complex class II expression21 and antibodies22, and
favour T helper 1 versus T helper 2 responses20. They
influence cytotoxic effects via cell death and oxidative
Indirect projections stress23, have a role in metabolic regulation through glu­
Neural pathways involving cose utilization and ATP production24 and interact with
at least one relay.
the major neurotransmitters and many secondary neuro­
Hypophyseal portal system peptidergic systems. As such, glucocorticoids modulate
The microcirculation that emotion and cognition, with key examples being learn­
allows transport of ing ability, performance, emotional perception and
hypothalamic hormones mood25,26. These interactions also exemplify how gluco­
to the pituitary gland.
corticoid therapy can result in multiple effects, including
Irradiance threshold unwanted adverse effects such as depression27–30.
The threshold power of (solar) CORT is a homeostatic anticipatory hormone that
electromagnetic radiation is secreted by the adrenal glands. Consequently, under
needed to exert an effect.
basal conditions it is released with a characteristic cir­
Stereotypic behaviours cadian pattern of secretion with high levels just before
Repetitive body movements waking (start of the active cycle), followed by a steady
that serve no biological decline down to trough (or nadir) levels during the sleep­
function. ing or inactive phase, hence anticipating the needs of the
Goal-​directed behaviours
body (Fig. 2a). The daily rhythm of CORT is regulated
Behaviours engaged for a through indirect projections from the SCN to the para­
specific functional purpose. ventricular nucleus (PVN) of the hypothalamus, which
inhibit corticotropin-​releasing hormone (CRH) and
arginine vasopressin (AVP) release during the inactive
phase of the cycle31,32. Furthermore, to produce appro­
priate reactivity to physiological, cognitive and emo­
tional stressors, the brain stem and limbic system also
modulate HPA activity via projections to the PVN33,34.
Axonal terminals in the median eminence release
CRH and AVP into the hypophyseal portal system where
they are transported to the pituitary and stimulate
pituitary corticotrophs to release adrenocorticotropic
hormone (ACTH). ACTH is released into the systemic
circulation and once at the adrenal cortex stimulates
the production of CORT. CORT undergoes de novo
synthesis and release back into the systemic circulation,
enabling it to travel to its target tissues and produce its
characteristic metabolic, cardiovascular, immunological
and cognitive effects33. CORT also acts via an autoregu­
latory negative feedback loop and inhibits HPA activity
via effects at the level of the pituitary, hypothalamic PVN
and hippocampus35.
Further levels of circadian control exist, including
splanchnic nerve innervation of the adrenal glands36.
The adrenal glands receive autonomic (sympathetic)
innervation via neuronal projections of the autonomic
portion of the PVN36,37, which alters adrenal cortical
sensitivity to ACTH with a reduction in responsive­
ness during the circadian nadir. CORT synthesis and
adrenal clock gene functioning is also influenced by a
light-​sensitive mechanism that occurs across the 24-h
period, with a shift in irradiance threshold according to
the time of day. Thus, in mice housed in complete dark­
ness, although high-​intensity light activated cortico­
sterone at all times of day, lower intensity light had no
effect during the subjective day. The adrenal response
therefore is dependent on both irradiance and circadian
phase38,39. The adrenal gland itself also has an autono­
mous clock that regulates ACTH sensitivity and steroido­
genesis, allowing it to fine tune its own homeostatic
control40,41. Finally, peripheral CLOCK-​mediated acetyl­
ation of the glucocorticoid receptor can decrease tissue
sensitivity to glucocorticoids in a circadian manner42.
These circadian fluctuations in activation of gluco­
corticoid receptors also have important interactions
with multiple other crucial homeostatic processes,
including the transcriptional activity of other genes that
respond to glucocorticoids and their corresponding
physiological outputs, such as physical activity and body
temperature5,43. For example, in the rat, glucocorticoid-​
responsive tryptophan hydroxylase 2, a gene impli­
cated in physical activity, temperature and emotional
response, has a circadian rhythmicity that is abolished
by exogenous steroids44.
Stress response
Acute stress. The acute response to stress is a dyna­mic
process that changes over time, starting with stereotypic
behaviours and then changing to goal-directed behaviours
specific to the stressor, followed by activation of the
SAM within seconds and finally recruitment of the HPA
axis, with peak levels of cortisol occurring between
15 and 20 min after stress onset45. These early responses
provide increased energy resources and initiate longer
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Chronic stress. In response to chronic stress, a dynamic

Light Dark Hypothalamus change in the ratio of AVP to CRH in the hypothalamic
PVN
Suprachiasmatic PVN occurs49 as well as an associated decreased sen­
nucleus sitivity to the glucocorticoid feedback50. Obstructive
sleep apnoea is a good example of chronic stress (Fig. 2c).
In sleep apnoea, there is a marked increase in the amount
of cortisol released during each secretory pulse, which
Neuron normalizes after continuous positive airway pressure
treatment51. In critical illness, the situation is somewhat
different with the increased levels of cortisol produced
by long-​term stress being present for the first few days
Cortisol
secondary to increased adrenal sensitivity to ACTH and
increased cortisol synthesis47. During long-​term critical
Adrenal illness, a further change in HPA axis regulation occurs
gland
with reduced cortisol metabolism becoming an increas­
ingly important factor in maintaining raised levels of
plasma cortisol52,53.
Anterior Posterior
pituitary pituitary Glucocorticoid signalling. Glucocorticoid receptors
gland gland (GRs) and mineralocorticoid receptors (MRs) are the
cognate intracellular nuclear receptors for CORT54.
The affinity of CORT for MR is approximately fivefold to
ACTH tenfold higher than that for GR55. Binding of CORT to its
receptors leads to either transactivation or repression of
genomic transcription as well as more rapid nongenomic
effects56,57. Nongenomic signalling is mediated via clas­
Other sic58 or membrane-​bound variants of the receptors59,60.
Immune Peripheral
homeostatic
function clocks The membrane-​bound variants have lower glucocor­
signals
ticoid affinity than their classic nuclear counterparts61.
Nuclear MR are generally constantly occupied during
the day and only become unoccupied at the very low
levels of CORT found at night in humans or during the
Cognition Cardiovascular Metabolism
day in rodents. As CORT levels rise to a critical threshold
(as seen during the circadian peak or following acute or
chronic stress), nuclear GR and membrane-​associated
MR and GR occupation occurs54. It is important to note
that the one exception to this effect is the hypothalamic
Fig. 1 | coordination of central and peripheral clocks by glucocorticoids. The
supra­chiasmatic nucleus central clock receives light–dark signals that, in turn, influence SCN, which does not appear to be regulated by circu­
hypothalamic–pituitary–adrenal and sympatho–adrenomedullary activity leading to lating CORT62. As such, the SCN is the one place where
circadian CORT production. CORT activates glucocorticoid receptors in peripheral tissues, endogenous CORT cannot shift clock function. Whether
which synchronizes peripheral clocks and downstream metabolic, cardiovascular, neuronal this feature is due to a lack of corticosteroid receptors or
and immune pathways. Other Zeitgebers such as food, temperature and social cues can also altered chromatin structure is unclear.
entrain or influence the entrainment of clocks and can alter the output of these downstream A further level of regulatory control is the tissue
pathways. ACTH, adrenocorticotropic hormone; PVN, paraventricular nucleus. specificity of GR and MR distribution. GR are present
throughout the brain and peripheral tissues while MR
term and slower genomic effects that restrain inflam­ have more limited localization, predominately being
matory and other potentially dangerous responses46. The found in cardiovascular tissue, liver and kidneys, as well
response to the acute stress of cardiac surgery can be as corticolimbic regions of the brain54. Although GR are
seen in Fig. 2b (ref.47). This response is very interesting present throughout the brain, only the hippocampus,
for several reasons. First, despite the greatly increased basal ganglia, lateral septum and medial amygdala neu­
levels of cortisol, the pattern of cortisol secretion rons present a high MR:GR ratio63. As these areas do not
remains pulsatile. Second, despite initial high levels of express 11β-​hydroxysteroid dehydrogenase (11β-​HSD)
ACTH, these rapidly fall to basal levels while the cor­ type 2 (discussed in detail in a subsequent paragraph),
tisol level remains raised. Despite this fall in ACTH MR are persistently occupied even during the circa­
levels, small changes in these basal levels of ACTH ini­ dian nadir and it is GR and the fast-​acting nongenomic
tiate large pulses of cortisol release, indicating a rapidly response of the lower affinity membrane-​bound MR
induced increased sensitivity of the adrenal cortex to that respond when CORT levels rise in response to a
ACTH. This effect has now been investigated in reverse stressor28. This response helps to prepare an individual
translation studies in rats and complemented with mathe­ to respond to a stressor through enhancing synaptic
matical modelling, which has enabled the importance plasticity at a cellular level, which leads to a behavioural
of the dynamic adrenal steroidogenic regulatory network change in the form of altered decision making, atten­
to be characterized48. tional bias and risk assessment64. Although other brain

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a Normal conditions in a healthy volunteer c Chronic stressor: obstructive sleep apnoea

Mean circadian Ultradian
cortisol ACTH Cortisol 600 Baseline
60
50 500 600

Cortisol (nmol/l)

Serum levels of cortisol

ACTH (pg/ml)
40 400 500
30 300 400

(nmol/l)
20 200 300
10 100
200
0 0
100
0
0
0
0
0
0
0
0
0
0
0
0
0
:0
:0
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19
21
23
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03
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0
Time (24 h)

b Acute stressor: cardiac surgery

1,500 1,000 600

Serum levels of cortisol

1,250 500
800

Cortisol (nmol/l)
ACTH (pg/ml)

1,000 400

(nmol/l)
600
750 300
400 200
500
250 200 100
0 0 0
0 0 0 0 0 0 0 0
:0 2:2 1:4 6:0 9:2 1:4 5:0 8:2
4
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4
4
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2 0 0 0 1 1 1
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Time (24 h) Time (24 h)

Fig. 2 | Human cortisol ultradian rhythmicity under basal and stressful conditions. Cortisol is secreted in a circadian
rhythm characterized by a nadir or quiescent phase during the inactive period (overnight while sleeping in humans).
An anticipatory rise in CORT levels occurs before waking followed by the circadian peak of secretion at the start of
the active period. Underlying this rhythm, however, is a complex and dynamic ultradian rhythm consisting of pulses
approximately every 3 h. a | A schematic representation of a circadian and ultradian cortisol rhythm from a healthy male
volunteer. b | The effect of acute stress during cardiac surgery (the shaded area shows when coronary artery bypass
grafting occurred). Cortisol levels remain elevated throughout the sampling period. This occurs via an initial surge in
adrenocorticotropic hormone (ACTH), followed postoperatively by altered adrenal sensitivity to ACTH. c | The effect of
chronic stress on hypothalamic–pituitary–adrenal axis activity in the form of obstructive sleep apnoea. Here, disordered
cortisol pulsatility is seen in the form of an increase in the number of pulses and the amount of cortisol secreted per pulse
at baseline (before continuous positive airway pressure (CPAP) therapy), especially over the quiescent period when
endogenous cortisol levels naturally fall. The profiles improve after 3 months of CPAP therapy. Parts a and b are modified
with permission from Wolters Kluwer, Gibbison, B. et al. Dynamic pituitary–adrenal interactions in response to cardiac
surgery. Crit. Care Med. 43, 791–800 (2015)47. Part c is adapted with permission from ref.51, Oxford University Press.

areas can still respond to changes in CORT this will
only be through their genomic and nongenomic GR65.
Consequently, this region specificity in receptor distri­
bution will modify corticosteroid signalling, including
the activation and termination of stress responses, and is
likely to be important for promoting long-​lasting adap­
tive protective mechanisms such as strategic planning
and memory storage and consolidation66.
Other layers of regulatory control arise through avail­
ability of CORT. CORT is highly lipophilic, which means
that under basal conditions 90% of CORT is tightly
bound to the high-​affinity, limited-​capacity protein car­
rier corticosteroid-​binding globulin (CBG)67,68. Around
4–5% is loosely bound to albumin and the remaining 5%
of CORT is ‘free’ and biologically active69. CBG levels are
controlled by a variety of different factors such as genetic
variability, liver and thyroid function, nutritional status,
inflammation and stress. Additionally, CBG is saturated
at fairly low CORT concentrations, including under basal
(nonstressed) levels found at the circadian peak. Similar
to CORT, CBG exhibits homeostatic diurnal varia­tion70,
the resultant effect being a higher proportion of free
(and therefore biologically active) CORT during the cir­
cadian peak, which accentuates the diurnal profile of free
CORT and the response to stress. CBG also acts as a car­
rier to specific target sites (such as sites of inflammation)
and even acts as a protein thermocouple releasing CORT
at sites of increased temperature71. CBG concentrations
are therefore of great importance for the bioavailability
of CORT and its ability to act at a tissue level72.
The metabolic clearance of CORT occurs through
two mechanisms, enzymic degradation in the liver72,73
and intracellular metabolism by the two isoenzymes of
11β-​HSD, which catalyse the interconversion of active
CORT and the inert forms, cortisone (human) and
11-dehydrocorticosterone (rodents). 11β-​HSD type 1 is
predominately a reductase that catalyses the regenera­
tion of active glucocorticoids, which amplifies the cel­
lular actions of CORT73. It is widely expressed in liver,
adipose tissue, muscle, pancreatic islets, adult brain,
inflammatory cells and gonads74. 11β-​HSD type 1 there­
fore increases tissue levels of CORT and is thought to be
a major factor in regulating tissue sensitivity to CORT,
especially under conditions that can increase 11β-​HSD

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Hypothalamus loss of circadian rhythmicity, but the underlying pulsa­

tility of CORT remains79. Nor does the ultradian rhythm
arise as one would expect from a central hypothalamic
‘pulse generator’, as pulses of CRH do not induce down­
Anterior
pituitary stream pulses of ACTH and CORT80. Mathematical
Cortisol
gland modelling techniques have consequently been utilized,
which predict that the ultradian rhythm has a subhy­
Adrenal Posterior
gland pituitary pothalamic origin62. Here, a dynamic feedforward–
gland feedback communication exists between ACTH on
ACTH the adrenal cortex and endogenous glucocorticoids
on the pituitary corticotrophs, together driving ultradian
rhythmicity with a natural delay between ACTH acti­
vating adrenal melanocortin 2 receptors, glucocorticoid
Adrenal delay biosynthesis and cortisol release (Fig. 3). This prediction
Cholesterol was subsequently confirmed in our rat model62.
MC2R
The adrenal gland itself preferentially responds to
oscillatory ACTH signals; in rodents whose endoge­
nous ACTH is suppressed with exogenous glucocor­
ticoids, pulsatile ACTH infusions result in pulsatile
corticosterone secretion whereas constant ACTH infu­
sions of the same total dose result in no response81.
Mitochondrion Additionally, the adrenal gland has its own internal feed­
forward–feedback system that amplifies the response
to rapid changes in ACTH level, sensitizing the adre­
nal glands to oscillating levels of ACTH and hence
alterations in CORT82.
Fig. 3 | Schematic representation of the hypothalamic–pituitary–adrenal axis
showing natural inbuilt adrenal delays. After release from the pituitary gland, Effect of hormone oscillation. Both circadian and ultra­
adrenocorticotropic hormone (ACTH) binds to adrenal melanocortin 2 receptors dian oscillations in hormone levels matter. Between
(MC2Rs). Here, natural inbuilt delays occur ; MC2R binding leads to increased uptake 5% and 20% of cells show clear circadian oscillations in
of cholesterol, which is the precursor for all steroid hormones. Cholesterol then mRNA levels12 and circadian fluctuations are found at
undergoes a series of biosynthetic steps before being transported into mitochondria, almost every stage of gene expression83 and have been
undergoing hydroxylation and the subsequent release of cortisol into the circulation. associated with important biological effects. In trans­
genic mice, if circadian peak levels of CORT are admin­
type 1 activity such as visceral obesity72. In addition, istered during a motor learning task, these mice show
11β-​HSD type 1 is thought to mediate many cognitive increased memory of motor skills84. This effect arises sec­
and metabolic effects of CORT excess. For instance, ondary to a rapid GR-​mediated nongenomic mechanism
11β-​HSD type 1 deficiency in rodents protects against via LIM kinase signalling that increases numbers of new
age-​related and stress-​related cognitive decline while neuronal spines. Low trough levels of CORT are then
transgenic overexpression exacerbates cognitive impair­ needed to retain and stabilize the memory. This reten­
ment75. The other isoform, 11β-​HSD type 2, is a high-​ tion and stabilization involves ‘pruning’ of old spines via
affinity dehydrogenase that inactivates glucocorticoids an MR-​mediated pathway that alters gene expression,
and is particularly important in the kidney, where it which implies that circadian fluctuations are required
protects mineralocorticoid receptors from activation for plasticity in learning and memory84. Indeed, clini­
by the much higher concentration of cortisol73. More cally this phenomenon is nothing new; in patients tak­
studies are needed to define how tissue ratios of cortisol ing glucocorticoid-​based therapeutics and in those with
and cortisone might change during stress and whether Cushing syndrome, both situations with chronically ele­
this might provide yet another mechanism to guard our vated glucocorticoid levels and/or no oscillations, there
homeostatic state. are marked impairments in learning and memory25.
What we are beginning to understand is that circa­
Ultradian rhythm. Underlying the circadian rhythm there dian rhythmicity is only the tip of the iceberg, and func­
is a complex and dynamic ultradian rhythm comprised tionally important dynamic changes are seen in a shorter
of discrete pulses of secretion of both ACTH and cor­ time frame than can be described by simple circadian
tisol (Fig. 2a). This pulsatile pattern has an approximate alterations. In the HPA axis, ultradian hormone pres­
frequency of 60–90 min with increased pulse amplitude entation is essential for physiological gene functioning85.
and frequency at the circadian peak76. Patterns of secre­ Very different patterns of gene activation are seen both
tion of ACTH and cortisol are influenced by a multitude in vitro and in vivo depending on the pattern of hormone
of factors, including genetics, sex hormones, epigenetic presentation86. Ultradian oscillations in glucocorticoid
influences, environmental stressors and age, which leads levels result in a phenomenon known as gene pulsing
Circadian rhythm
Any biological process that
to individual diversity77,78. Unlike circadian rhythms, the (Fig. 4a). This phenomenon is specific for the endoge­
displays an oscillation of origin of the ultradian rhythm is not from central SCN nous glucocorticoid hormones as synthetic glucocorti­
approximately 24 h. regulation; rodents with SCN lesions show an isolated coids have long binding characteristics at the GR and

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cannot cycle on and off86. As CORT levels rise, as is seen
in endogenous glucocorticoid pulsatility, GR binding
and activation occurs followed by nuclear translocation,
dimerization and interaction with DNA glucocorticoid
response elements, which initiates transcription. Next,
rapid cycling of GR and transcription factors on and off
chromatin occurs. Once CORT levels decline, as seen
in pulse termination, GR dissociates from DNA and
is released back into the nucleoplasm ready to rapidly
respond to subsequent CORT pulses. If the same dose of
CORT is used but is presented as a constant as opposed
to a pulsatile pattern of presentation, genomic reactivity
changes lead to altered transcriptional activity86,87 as well
as differential gene responses86 (Fig. 4b). In addition to

a Gene pulsing b Cell culture (Tsc22d3)

Pulses of corticosterone 25 Pulsed Constant
GR–DNA binding
Per1 nascent RNA
15.0 20
1,500
12.5
corticosterone (ng/ml)

Fold change
1,250 15
Plasma levels of

Fold induction
10.0
1,000

750 7.5 10

500 5.0
5
250 2.5

0 0 0
0 30 60 90 120 150 180 C P1 W1 P2 W2 P3 W3 P4 W4 P5 W5 P6 W6 P7 W7 P8 W8
Time (min)

c Animal model — rodent amygdala d Human model — BOLD fMRI responses to FERT
P < 0.05 Nonpulsatile Pulsatile glucocorticoid Attentional bias towards
glucocorticoid rhythm rhythm emotional faces
30 50 P = 0.014
P < 0.01

Vigilance scores
Grey values (arb. units x104)

25
P < 0.01

20

15 Striatum
Insula

y
10
rfu

rfu
pp

pp
a

a
Ha

Ha
Fe

Fe
5
Nonpulsatile Pulsatile
0
Recognition of emotional faces
Vehicle 80
Amygdala
Constant
Accuracy (%)

P = 0.01

50 ng/ml corticosterone Uncertainty in identifying

emotional valence
50 ng/ml corticosterone

100 ng/ml corticosterone ve tiv

e ve tiv
e
siti ga siti ga
Po Ne Po Ne
100 ng/ml corticosterone
Nonpulsatile Pulsatile

Fig. 4 | The importance of gene pulsing. a | In adrenalectomized rats,
hourly pulses of corticosterone result in a similar pattern of association–
dissociation kinetics in glucocorticoid receptor (GR)–DNA binding and
downstream cyclic recruitment and pulsatile release of the clock gene Per1
nascent RNA. This effect is not seen with synthetic glucocorticoid
treatment. b | Ultradian and constant corticosterone treatments have
different effects on transcription of Tsc22d3, a GR-​regulated gene. Here,
pulsatile presentation shows a pulsatile pattern of gene fold induction,
while constant infusion induces constant RNA release. c | Adrenalectomized
rats received either pulsatile corticosterone (50 ng/ml or 100 ng/ml peaks)
or constant corticosterone (12-h constant infusion clamped at 50 ng/ml).
They then underwent a 10-min noise stress. c-​fos mRNA expression was
analysed in different brain regions. A differential response was found in the
pituitary , amygdala, hippocampus and paraventricular nucleus. The effect
shown was dependent on both phase and amplitude of the glucocorticoid
pulse, which suggests that a differential response is seen in stress circuitry
depending on the pattern of exposure. d | Healthy human male volunteers
underwent a chemical adrenalectomy with metyrapone. Data from
ref. 93. In a cross-​over trial design they then received hydrocortisone
replacement therapy (total daily dose 20 mg) as either standard oral
(three times a day), constant circadian subcutaneous infusion or constant
pulsatile subcutaneous infusion for 5 days. On day 5, participants
underwent functional MRI (fMRI) while performing a facial expression
recognition task (FERT). Blood-​oxygen-level-​dependent (BOLD) imaging
showed a differential response in attentional bias and recognition of
emotional faces depending on whether a pulsatile or a nonpulsatile
pattern of glucocorticoid presentation was used. Communication
networks within the insula, striatum and amygdala also varied depending
on whether the presentation was pulsatile or nonpulsatile. C, control;
P, induction; W, withdrawal. Parts a and b are reproduced from ref. 86,
Springer Nature Limited. Part c is adapted with permission from ref.91,
Oxford University Press.

www.nature.com/nrendo
 Reviews

the classic glucocorticoid response element-​dependent making and alertness and stimulates cognitive function­
interactions, GR can also interact with a variety of other ing. CORT also has a proinflammatory effect, resulting
transcription factors and influence transcription via in an increased response to infection99. Chronic expo­
protein–protein interactions88,89 and chromatin remodel­ sure to stress results in reversal of the beneficial effects
ling88,90. These pattern-​dependent interactions have seri­ with long-​term cortisol exposure becoming maladaptive,
ous implications for therapeutics based on continuous which leads to a broad range of symptoms and disease
exposure to glucocorticoids, and probably contribute to states, including the metabolic syndrome, obesity, can­
the adverse effects of these drugs16. cer, mental health disorders, cardiovascular disease and
Downstream, constant and pulsatile patterns of increased susceptibility to infections10,11,54,100,101.
CORT result in differential neuronal and behavioural With regard to immune functioning, components of
responses. For instance, noise stress induces neuronal both the adaptive and innate immune system undergo cir­
activation of c-​fos in the amygdala, hippocampus and cadian variations in levels and functionality to optimize
hypothalamic PVN. Interestingly, the pulse phase is cru­ response and recovery to a pathogen102. Autonomous
cial for this response. If the noise is administered during circadian clocks are also found in different subsets of
the rising phase, the c-​fos response in the amygdala is immune cells, including macrophages and lympho­
increased (Fig. 4c). This effect is paralleled by differen­ cytes103,104. CORT also has a multitude of effects on the
tial behavioural responses to the stressor. Importantly, immune system20. Chronic increases in CORT, either as
the effect is reproducible with the pulse phase depend­ a result of the effect of the steroid or the development of
ency pattern being recorded in aggressive and novelty glucocorticoid resistance101, increases susceptibility to
behaviour responses to glucocorticoids, as well as in infection20. Chronic stress can impair GR function as a
the neuroendocrine mechanism of rapid HPA negative result of long-​term exposure to the resultant release of
feedback91,92. Translational studies in humans have found proinflammatory cytokines. Indeed, cytokines (along with
similar results (Fig. 4d). Healthy male volunteers on a their signalling pathways including, but not limited to,
block and replace regimen of endogenous glucocorticoid mitogen-​activated protein kinases, NF-​κB and cycloox­
blockade with metyrapone and replacement therapy ygenase) inhibit GR function99. Potential mechanisms
with either circadian or ultradian subcutaneous hydro­ underlying this inhibition include disruption of GR trans­
cortisone or standard oral hydrocortisone therapy (three location, GR–DNA binding, GR–inflammatory media­
times a day) at the same total daily dose exhibit altered tor interactions and alterations in GR phosphorylation
cognitive and behavioural effects that are dependent on status105–107. Glucocorticoid resistance in turn interferes
the cortisol pattern. Specifically, a lack of physiological with HPA downregulation of the very same proinflam­
pulsatility was associated with poorer quality of sleep, matory cytokines and creates a vicious cycle. Thus, in
poorer working memory performance and altered accu­ the case of the common cold, an exaggerated response to the
racy in recognition and attentional bias toward or away symptoms and signs of the upper respiratory tract illness
from emotional faces93. is generated by the resultant proinflammatory response108.
Long-​term exposure to CORT also increases blood
Stress and disease levels of glucose109 and stimulates adipocyte precursor
Stress is any stimulus that disrupts or threatens homeo­ maturation, which promotes adiposity110. Adipose tissue
static balance. The stress response is a mechanism that is now seen as an active endocrine gland rather than a
can restore homeostatic processes and promote self-​ passive energy store as it produces a wide variety of hor­
preservation through a complex interaction between mones and regulatory factors72. The levels of these fac­
the HPA axis, central and peripheral autonomic nervous tors in turn reflect the metabolic status of the adipocytes
systems and immune systems15. The HPA axis responds and interact with homeostatic connections between adi­
to stress by rapidly releasing CORT. As CORT is highly pose tissue and the brain as well as other organs, which
lipophilic, it is not prestored in vesicles and is synthesized together control energy intake and expenditure72,111.
de novo in response to ACTH. During long-​term stress a Obesity is also linked to chronic low-​grade inflamma­
dissociation between ACTH and CORT secretion deve­ tion108 via tumour necrosis factor (TNF) and IL-6. TNF
lops94,95, predominantly via increased adrenal sensitivity inhibits intracellular insulin signalling pathways and
to ACTH48 or non-​ACTH-mediated mechanisms95. This IL-6 promotes atherosclerosis and metabolism of glucose
effect is seen in patients undergoing cardiac surgery, who and lipids111,112, all of which interact with the HPA axis20.
show a marked shift in adrenal responsiveness47 (Fig. 2b). Studies of an increasingly common stress-​associated
Reverse translation studies in animals suggest this shift problem — sleep deprivation — confirm elevated nadir
arises secondary to changes in the regulation of both stim­ CORT levels, which then acts as another risk factor for
ulatory and inhibitory intra-​adrenal signalling pathways47. insulin resistance113. Behaviourally, chronic sleep depri­
In models of inflammatory bowel disease and viral chal­ vation is associated with increased appetite and energy
lenges, IL-6 and ACTH-​independent immune–adrenal expenditure114. Chronic CORT exposure also stimulates
pathways have also been linked to this dissociation96,97. mesolimbic reward pathways within the brain, leading
The rapid rise in levels of CORT seen under condi­ to increased intake of palatable food such as sucrose
tions of stress increases the availability of supplemen­ solutions111. Additionally, increased feeding might be
tal energy stores by promotion of gluconeogenesis and stimulated by leptin and ghrelin levels115,116. During
inhibition of insulin production combined with vaso­ chronic stress, it is thought that these two hormones can
constriction, which aids delivery of blood to the mus­ no longer accurately signal caloric need117. The effect in
cles and the brain98. Centrally, CORT promotes decision this situation is a misperception of insufficient available

Nature Reviews | Endocrinology

Reviews

energy stores116. This effect is seen in combination with
increased proinflammatory cytokine levels28, which
makes it is unsurprising that chronic stress and chrono­
disruption are linked with the development of metabolic
complications.
Hypercortisolaemia is also linked with affective dis­
orders10,27. Mathematical modelling techniques have
shown that individuals with major depressive disorder
have disordered cortisol secretion with an increased
mass of cortisol in each pulse and increased pulse fre­
quency118. Patients with major depressive disorder have
long been known to exhibit glucocorticoid resistance
in the form of resistance of endogenous cortisol to sup­
pression in the dexamethasone and dexamethasone–
CRH suppression tests119, the results of which can pre­
dict clinical outcome120. Chronic exposure to stress
results in a degree of limbic system atrophy, a key region
involved in regulation of emotion 121. This effect is
also closely interlinked with immune function; stress-​
induced proinflammatory cytokines, including IL-1β,
IL-6 and TNF, are implicated in depressive behaviour
in rodent models of depression and in patients with
depression101,105,122,123. The mechanisms underlying this
connection are complex. It is possible that inflamma­
tion and glucocorticoid signalling might act on the same
processes to cause cumulative damage or that the dual
pro­inflammatory and anti-​inflammatory effects of gluco­
corticoids disrupt the immune system of the brain
in favour of inflammatory effects124. In patients with
depression, decreased T cell availability might arise sec­
ondary to increased apoptosis sensitivity combined with
impaired glucocorticoid responsiveness and reduced
brain trafficking capacity in response to the appro­
priate neuroendocrine or immune stimuli101,122. Stress
also enhances NF-​κB activation106,107,125; indeed, stress-​
induced anhedonia is directly linked to increased NF-​κB
activity105. Interestingly, antidepressants can enhance GR
functioning126 and inhibit cytokine pathways127.
These effects of glucocorticoids are usually accepted
as simply being due to the high levels found in the blood.
However, this theory might be an oversimplification.
In primary hypocortisolaemia (or Addison disease),
patients are treated with what we believe to be opti­
mal replacement of hydrocortisone three times a day
to mimic the circadian rhythm128,129. Despite this effort to
give physiological replacement, these patients have
increased mortality as a result of cardiovascular disease,
infectious disease and cancer, and increased morbidity
from fatigue and difficulties in concentrating130–132. This
therapy fails to provide the anticipatory rise in cortisol
before wakening and thus gives a shifted circadian pro­
file while also resulting in acute nonphysiological lev­
els of cortisol in the middle of the day133. Patients have
altered immune responses in the form of altered circa­
dian patterns of circulating monocytes and natural killer
cells134, impaired natural killer cell function135 and hypo­
methylated CD4+ T cells136. In an attempt to rectify these
adverse outcomes, modified and dual-​release prepara­
tions134,137,138, as well as continuous139 and pulsatile pump
(The Pulses Study; ISRCTN67193733) preparations, are
being trialled. Initial results are encouraging, with closer
mirroring of circadian profiling resulting in alterations
in clock gene function140 and improvements in immune
functioning134 and quality of life134,137,141,142. These issues
are not only limited to endogenous CORT, but also to
synthetic glucocorticoids16. These are some of the most
widely prescribed medications143,144 but, despite their
clinical efficacy, over three quarters of patients experi­
ence adverse effects even at what would be considered
a fairly low dose145,146. Chronic glucocorticoid treatment
can also induce glucocorticoid resistance in susceptible
patients with glucocorticoid-​responsive conditions such
as asthma or rheumatoid arthritis147.
Conclusions
Homeostatic processes are dynamic and interactive.
As society changes with the development of a 24-h world
and its use of social media and changes in interpersonal
communication, many of our evolutionarily adaptive
processes are in danger of becoming maladaptive. If we
are to understand the growing epidemic of stress-​related
human disease, we need to go back to first principles
and understand not only the mechanisms underlying the
regulation of our patterns of physiological activity and
hormone secretion — particularly over the important
and notoriously difficult nadir period during sleep —
but also why they are important for the maintenance of
health. If we are going to aspire to an objective of opti­
mal personalized medicine, we need to devise methods
not only to measure dynamic basal patterns of hor­
monal metabolic and immune functioning over the
whole day, but also novel therapeutic interventions to
counteract the causes of environmental-​related and/or
stress-​related illness.
Published online xx xx xxxx

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Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
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